[Acute liver injury with hepatic encephalopathy associated with gemcitabine administration for adjuvant chemotherapy in an HBV carrier with pancreatic cancer].

A 75-year-old woman was admitted to our department because of epigastric pain. Imagings revealed cancer of the head of the pancreas. She was an HBV carrier, although no liver dysfunction was observed. Her serum HBV-DNA level was lower than 2.6. We performed pancreaticoduodenectomy for pancreatic cancer. No postoperative complication was observed. The histopathological diagnosis was tubular adenocarcinoma of the pancreas. As a postoperative adjuvant chemotherapy, gemcitabine hydrochloride (GEM) was injected at a dose of 800mg/m2 once a week. Disorientation and jaundice were observed after six doses of GEM. Blood chemistry revealed that total bilirubin and ammonia were abnormally elevated, and that blood coagulant factors were diminished. Serum HBV-DNA level was lower than 2.6. It showed no reactivation of HBV. Abdominal CT showed no recurrence but fatty liver. Fresh frozen plasma was supplied and branched chain amino acids were injected after GEM was administration discontinued. Lactulose was also given orally. With these conservative treatments, she recovered completely. Careful monitoring of liver function during GEM administration is required in a HBV carrier.

HMGA1 is induced by Wnt/beta-catenin pathway and maintains cell proliferation in gastric cancer.

The development of stomach cancer is closely associated with chronic inflammation, and the Wnt/beta-catenin signaling pathway is activated in most cases of this cancer. High-mobility group A (HMGA) proteins are oncogenic chromatin factors that are primarily expressed not only in undifferentiated tissues but also in various tumors. Here we report that HMGA1 is induced by the Wnt/beta-catenin pathway and maintains proliferation of gastric cancer cells. Specific knockdown of HMGA1 resulted in marked reduction of cell growth. The loss of beta-catenin or its downstream c-myc decreased HMGA1 expression, whereas Wnt3a treatment increased HMGA1 and c-myc transcripts. Furthermore, Wnt3a-induced expression of HMGA1 was inhibited by c-myc knockdown, suggesting that HMGA1 is a downstream target of the Wnt/beta-catenin pathway. Enhanced expression of HMGA1 coexisted with the nuclear accumulation of beta-catenin in about 30% of gastric cancer tissues. To visualize the expression of HMGA1 in vivo, transgenic mice expressing endogenous HMGA1 fused to enhanced green fluorescent protein were generated and then crossed with K19-Wnt1/C2mE mice, which develop gastric tumors through activation of both the Wnt and prostaglandin E2 pathways. Expression of HMGA1-enhanced green fluorescent protein was normally detected in the forestomach, along the upper border of the glandular stomach, but its expression was also up-regulated in cancerous glandular stomach. These data suggest that HMGA1 is involved in proliferation and gastric tumor formation via the Wnt/beta-catenin pathway.

HMGA2 maintains oncogenic RAS-induced epithelial-mesenchymal transition in human pancreatic cancer cells.

Pancreatic cancer is a highly aggressive malignancy due to elevated mitotic activities and epithelial-mesenchymal transition (EMT). Oncogenic RAS and transforming growth factor-beta signaling are implicated in these malignant features. The mechanisms that underlie EMT need to be addressed since it promotes tissue invasion and metastasis. The high-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor that is primarily expressed in undifferentiated tissues and tumors of mesenchymal origin. However, its role in EMT in pancreatic cancer is largely unknown. Here we report that HMGA2 is involved in EMT maintenance in human pancreatic cancer cells. Specific knockdown of HMGA2 inhibited cell proliferation, leading to an epithelial-state transition that restores cell-cell contact due to E-cadherin up-regulation. Consistently, an inverse correlation between HMGA2-positive cells and E-cadherin-positive cells was found in cancer tissues. Inhibition of the RAS/MEK pathway also induced an epithelial transition, together with HMGA2 down-regulation. Transcriptional repressors of the E-cadherin gene, such as SNAIL, decreased after HMGA2 knockdown since HMGA2 directly activated the SNAlL gene promoter. The decrease of SNAIL after RAS/MEK inhibition was suppressed by HMGA2 overexpression. Further, let-7 microRNA-mediated HMGA2 down-regulation had no effect on the prevention of the transformed phenotype in these cells. These data shed light on the importance of HMGA2 in reversibly maintaining EMT, suggesting that HMGA2 is a potential therapeutic target for the treatment of pancreatic cancer.